Spinocerebellar Ataxia with Axonal Neuropathy

NORD gratefully acknowledges Ryuki Hirano, Mustafa A. M. Salih, Hiroshi Takashima, and Cornelius F. Boerkoel for assistance in the preparation of this report. Dr. Salih is a pediatric neurologist at King Saud University, Saudi Arabia. Drs. Hirano and Takashima are neurologists at Kagoshima University, Japan. Dr. Boerkoel is a medical geneticist at University of British Columbia, Canada.

Synonyms of Spinocerebellar Ataxia with Axonal Neuropathy

SCAN1

General Discussion

Spinocerebellar ataxia with axonal neuropathy (SCAN1) is a neurodegenerative disorder that is inherited in an autosomal recessive pattern. SCAN1 is characterized by late childhood-onset of a slowly progressive cerebellar ataxia, followed by areflexia and signs of peripheral neuropathy. Gaze nystagmus and cerebellar dysarthria usually develop after the onset of ataxic gait. As the disease advances, pain and touch sensation become impaired in the hands and legs; vibration sense disappears in hands and lower thigh. Individuals with advanced disease develop a steppage gait and pes cavus; and later become wheelchair dependent. Affected individuals have normal intellect and longevity.

Signs & Symptoms

SCAN1 is suspected in individuals with the following clinical features:

– Cerebellar ataxia and areflexia of late childhood (13 – 15 years)-onset followed by signs of peripheral neuropathy

– Slow progression

– Absence of oculomotor apraxia

– Absence of extra-neurological findings common in ataxia-telangiectasia (telangiectasias, immunodeficiency and cancer predisposition)

– Family history consistent with autosomal recessive inheritance

– MRI: Cerebellar atrophy especially of the vermis is present in all affected individuals

Causes

SCAN1 is inherited as an autosomal recessive disorder. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.

All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.

Biallelic mutations in the tyrosyl-DNA phosphodiesterase 1 (TDP1) gene are found in all individuals with SCAN1. The TDP1 gene encodes tyrosyl-DNA phosphodiesterase 1 (Tdp1) a DNA repair enzyme that is involved in correction of the DNA strand breaks in which the 3′ end is blocked by stalled topoisomerase I or phosphoglycolate. The histidine at amino acid residue 493 (His493) is a key residue in the active site of Tdp1 and its mutation impairs enzymatic activity. In particular, the p.His493Arg mutation identified in SCAN1 reduces enzymatic activity 25-fold and results in accumulation of topoisomerase I DNA complexes. Also, the mutant Tdp1 forms a prolonged covalent intermediate with the DNA.

Consistent with these in vitro studies, lymphoblastoid cells from persons with SCAN1 are more sensitive to the camptothecins and radiation. Despite these findings, SCAN1 does not appear to arise solely from deficient functional Tdp1 because Tdp1-deficient mice have normal growth and survival under ideal growth conditions although they are highly sensitive to the camptothecins and bleomycin. This suggests that, at least in mice and yeast, redundant pathways exist for Tdp1 and that this redundancy is sufficient under ideal conditions.

Further analysis suggests that the pathology of SCAN1 can be partially attributed to the prolonged covalent intermediate state formed by the p.His493Arg Tdp1 because murine and yeast cells expressing the ortholog of the human p.His493Arg Tdp1 are more sensitive to DNA damaging agents than are Tdp1-deficientl cells. This latter observation would also provide an explanation for the rarity of SCAN1 because recurrence of the disease would require recurrence of the p.His493Arg mutation or a functionally equivalent mutation. The autosomal recessive inheritance of a neomorphic mutation is explained by the finding that the covalent intermediate formed by p.His493Arg Tdp1 is rapidly repaired by wild type Tdp1.

Affected Populations

SCAN1 has been identified in a single Saudi Arabian family. It has not been identified in other ataxic individuals.

Related Disorders

Partial symptomatic overlap with SCAN1 can be seen in several spinocerebellar ataxias including ataxia oculomotor apraxia 1 (AOA1), ataxia oculomotor apraxia 2 (AOA2), Friedreich ataxia (FRDA) and ataxia with vitamin E deficiency (AVED). AOA1 is characterized by early onset cerebellar ataxia, axonal neuropathy, oculomotor apraxia and chorea or dystonia. Serum concentration of albumin is decreased and total cholesterol is increased. The presence of oculomotor apraxia (80% of individuals with AOA1) differentiates AOA1 from SCAN1; however, this sign is not obvious in the early stages of the disease. AOA1 is caused by mutations of APTX.

AOA2 is characterized by early onset cerebellar ataxia, axonal neuropathy, oculomotor apraxia and chorea or dystonia. Serum concentration of alpha-fetoprotein (AFP) is increased. AOA2 is caused by mutations of SETX.

FRDA is characterized by slowly progressive ataxia of gait and limbs, extensor plantar responses, and is regularly accompanied by dysarthria and axonal (predominantly sensory) neuropathy. Areflexia and reduced vibration or position sense of the lower limbs are frequent signs. Progressive scoliosis and sensorineural hearing loss are common. The onset is usually before age 25 years (mean ranging between 11 and 20 years). FRDA can be distinguished from SCAN1 by the presence of extensor plantar responses, cardiomyopathy (detected by ECG or echocardiography), and/or the usual absence of cerebellar atrophy on CT/MRI. Molecular genetic testing of FRDA is helpful for diagnostic confirmation.

AVED is characterized by cerebellar ataxia, loss of proprioception and areflexia associated with markedly reduced plasma vitamin E (alpha-tocopherol) concentration. AVED can be treated by vitamin E supplementation. The diagnosis can be confirmed by identification of mutations in TTPA, the gene encoding the alpha-tocopherol transfer protein.

Diagnosis

The diagnosis of SCAN1 is made on history and clinical signs as listed above. DNA testing for mutations in TDP1 is only available on a research basis.

Standard Therapies

Treatment

Treatments are selected to address individual symptoms as they develop. Prostheses, walking aids, and wheelchairs are helpful for mobility depending on disabilities. Physical therapy may be helpful to maintain a more active lifestyle. Based on the proposed mechanism of disease, decreasing the predisposition of topoisomerase I to become trapped on the DNA might slow the progression of disease. Since oxidative damage of DNA is one factor that increases the amount of topoisomerase I stalled on the DNA, antioxidants may prove efficacious in affected individuals although this therapy has not been tried yet.

Investigational Therapies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222

TTY: (866) 411-1010

Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:

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